Lazaroids enhance skeletal myogenesis in primary cultures of dystrophin-deficient mdx mice

Metzinger, Laurent; Passaquin, Anne-Catherine; Vernier, Aline; Thiriet, Nathalie; Warter, Jean‐Marie; Poindron, Philippe

doi:10.1016/0022-510x(94)90263-1

Cited by 11 publications

(5 citation statements)

References 41 publications

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“…a Ca2 +-ATPase, could be altered. Moreover prevention of oxidative damage to the cell membrane by PDN cannot be excluded since lazaroids, which are structurally related to PDN and are known antioxidants, exert similar effects on skeletal myogenesis (Metzinger et al, 1994;Vernier et al, 1995). Finally, a membrane stabilizing effect of PDN has been reported (Massa et al, 1975) which could also play a role in the observed decrease in [Ca2+]C (this study and and Ca2+ fluxes across the sarcolemmal membrane of C2 myotubes .…”

Section: Lowering Of [Ca2"]c By Incubation Of Primary Cultures Withmentioning

confidence: 72%

Regulation of cytosolic calcium in skeletal muscle cells of the mdx mouse under conditions of stress

Leijendekker

Passaquin

Metzinger

et al. 1996

British J Pharmacology

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1 In Duchenne muscular dystrophy (DMD) dysregulation of cytosolic calcium appears to be involved in the degeneration of skeletal muscle fibres. Therefore, we have studied the regulation of the free cytosolic calcium concentration ([Ca2+]) under specific stress conditions in cultured myotubes isolated from the hind limbs of wild-type (C57BL10) and dystrophin-deficient mutant mdx mice. [Ca2+] [Ca2+]c when the cells were exposed to the hypo-osmotic buffer (100 mOsm).5 Incubation of the cell culture for 3-5 days from the onset of induction of myotube formation with the membrane permeable protease inhibitor, calpeptin (50 gM) abolished the rise in [Ca2+]c in mdx myotubes upon exposure to hypo-osmotic shock.6 Treatment of the cell culture for 3-5 days with ac-methylprednisolone (PDN, 10 guM) attenuated the rise in [Ca2+]c following hypo-osmotic stress for both normal and mdx myotubes by about 50%.7 The results described here suggest an increased permeability of mdx myotubes to Ca2+ under specific stress conditions. The ameliorating effect of PDN on [Ca2+]c could explain, at least partly, the beneficial effect of this drug on DMD patients.

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Section: Lowering Of [Ca2"]c By Incubation Of Primary Cultures Withmentioning

confidence: 72%

Regulation of cytosolic calcium in skeletal muscle cells of the mdx mouse under conditions of stress

Leijendekker

Passaquin

Metzinger

et al. 1996

British J Pharmacology

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“…the third day in culture (unless specified otherwise) and Ca 2+ influx was measured on day 7. This represents the optimal time for PDN (Metzinger et al , 1993; Passaquin et al , 1993) and lazaroids (Metzinger et al , 1994) to develop their effects on skeletal muscle cell differentiation. Oxidants were also tested acutely (i.e.…”

Section: Methodsmentioning

confidence: 99%

“…PDN was also able to enhance utrophin expression (Passaquin et al , 1993; Pasquini et al , 1995) and to enhance in vitro differentiation (Braun et al , 1989; Kaplan et al , 1990; Metzinger et al , 1993; Passaquin et al , 1993). Lazaroids, a class of antioxidant compounds structurally related to PDN, exhibit the same action as PDN on in vitro skeletal muscle cell differentiation (Metzinger et al , 1994).…”

Section: Introductionmentioning

confidence: 99%

Calcium influx inhibition by steroids and analogs in C2C12 skeletal muscle cells

Passaquin

Lhote

Rüegg

1998

British J Pharmacology

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1 Glucocorticoids, namely a-methylprednisolone (PDN) and de¯azacort, are the only drugs reported to have a bene®cial e ect on the degenerative course of Duchenne muscular dystrophy (DMD). Increased cytosolic calcium concentrations ([Ca 2+ ] c ) have been implicated as one of the pathological events responsible for the degeneration of dystrophic skeletal muscles. In previous studies, we have demonstrated that PDN treatment of both normal and dystrophic murine skeletal muscle cells was able to normalize elevated [Ca 2+ ] c and improved myogenesis. Here we have investigated the mechanism underlying the e ects of glucocorticoids on cellular Ca 2+ in¯ux into C2C12 skeletal muscle cells. 2 Long-term incubation of C2C12 myocytes with PDN was necessary to observe a reduction of 45 Ca 2+ in¯ux. PDN was most e ective in inhibiting 45 Ca 2+ uptake when added for 4 days (at the time of fusion of myoblasts into myotubes) and to a lesser extent, when added after fusion. It was ine ective when added to C2C12 cells at the myoblast stage. Short PDN incubation times, at the time of fusion were insu cient to elicit a response. 3 Several steroids were tested for their ability to inhibit 45 Ca 2+ in¯ux in C2C12 myocytes. All four glucocorticoids examined were able to reduce Ca 2+ in¯ux, dexamethasone being the most potent (IC 50 3.14+0.34610 78 M). Mineralocorticoids (aldosterone and 11-deoxycorticosterone) were also able to reduce Ca 2+ in¯ux. 4 The vitamin E-derived lazaroid U-83836E and the glucocorticoid-derived lazaroid U-74389G also elicited a decrease in Ca 2+ in¯ux, but higher concentrations were necessary. Because both glucocorticoids and lazaroids display antioxidant properties, but U-83836E is devoid of glucocorticoid activity, the reduction in Ca 2+ in¯ux was suspected to be triggered via an antioxidant mechanism. 5 To test this hypothesis, we assessed the action of several antioxidants, such as vitamin E, vitamin C, 2-tert.-butyl-4-methoxyphenol (BHA), 2,6-di-tert.-butyl-4-methyl-phenol (BHT) and nordihydroguaiaretic acid (NDGA), on 45 Ca 2+ in¯ux. None of these agents had an e ect on 45 Ca 2+ in¯ux. In addition, several oxidants were tested (either acutely or chronically) for their ability to elicit 45 Ca 2+ in¯ux in C2C12 myocytes and were found to be inactive. 6 The involvement of the glucocorticoid receptor on the modulation of Ca 2+ in¯ux was investigated. The glucocorticoid receptor antagonist mifepristone (code name RU38486, 10 76 M) caused a shift of two orders of magnitude of the PDN response. However, neither actinomycin D nor cycloheximide a ected the response to PDN. 7 Results with the phospholipase A 2 inhibitor, manoalide, suggest that glucocorticoid-induced protein synthesis (e.g. enhanced stimulation of lipocortin) does not play a role in the reduction of calcium in¯ux. 8 Our results suggest that steroids elicit a decrease in calcium in¯ux in C2C12 skeletal muscle cells. This decrease is not due to an antioxidant mechanism or to a mechanism which requires gene expression. Since mineralocorticoids and U...

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“…A recent report has shown that inhibition of lipid peroxidation with IRFI-042, a potent antioxidant, inhibited NF-B activity and TNFexpression in mdx mice along with improved strength measurements and decreased creatine kinase, and muscle necrosis [58]. These data support multiple reports of a variety of antioxidants, including lazaroids, to suppress the immune response by inhibiting NF-B activity [59][60][61][62][63][64][65]. Inhibition of NF-B resulted in reduced TNF-, IL-6 and iNOS levels suggesting an overall suppression of the immune response.…”

Section: Lazaroidsmentioning

confidence: 63%

“…Similarly, lazaroids also inhibit calcium influx in muscle cells but with less potency than prednisolone. Both lazaroids and prednisolone have been shown to enhance myogenesis of dystrophin deficient mouse skeletal muscle cells as determined by increase in the number of myotubes, acetylcholine receptors and -actinin without affecting myotube size [59]. It can be hypothesized that dystrophin-deficient muscle treated with lazaroids would decrease cytosolic calcium and reduce lipid peroxidation and that these events may facilitate myogenesis.…”

Section: Lazaroidsmentioning

confidence: 98%

Glucocorticoid Analogues: Potential Therapeutic Alternatives for Treating Inflammatory Muscle Diseases

Reeves

Rayavarapu²,

Damsker³

et al. 2012

EMIDDT

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Glucocorticoids (GCs) have been prescribed to treat a variety of diseases, including inflammatory myopathies and Duchenne muscular dystrophy for over 50 years. However, their prescription remains controversial due to the significant side effects associated with the chronic treatment. It is a common belief that the clinical efficacy of GCs is due to their transrepression of pro-inflammatory genes through inhibition of inflammatory transcription factors (i.e. NF-κB, AP-1) whereas the adverse side effects are attributed to the glucocorticoid receptor (GR)-mediated transcription of target genes (transactivation). The past decade has seen an increased interest in the development of GR modulators that maintain the effective anti-inflammatory properties but lack the GR-dependent transcriptional response as a safe alternative to traditional GCs. Many of these analogues or "dissociative" compounds show potential promise in in vitro studies but fail to reach human clinical trials. In this review, we discuss molecular effects of currently prescribed GCs on skeletal muscle and also discuss the current state of development of GC analogues as alternative therapeutics for inflammatory muscle diseases.

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Lazaroids enhance skeletal myogenesis in primary cultures of dystrophin-deficient mdx mice

Cited by 11 publications

References 41 publications

Regulation of cytosolic calcium in skeletal muscle cells of the mdx mouse under conditions of stress

Regulation of cytosolic calcium in skeletal muscle cells of the mdx mouse under conditions of stress

Calcium influx inhibition by steroids and analogs in C2C12 skeletal muscle cells

Glucocorticoid Analogues: Potential Therapeutic Alternatives for Treating Inflammatory Muscle Diseases

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